Lymphocytes demonstrate an enhanced 3-hydroxy-3-methylglutaryl coenzyme A reductase activity following mitogenic or antigenic stimulation. Since this enzyme is responsible for making mevalonic acid, it is generally assumed that mevalonate is required to initiate DNA replication. It is not known, however, whether mevalonic acid per se is necessary, or whether it is a precursor for an essential isoprenoid compound. This proposal describes experiments directed towards the identification of mevalonate-derived end products in murine lymphocytes which the aim of determining which isoprenoids are involved in the activation and effector stages of B and T lymphocytes. A similar requirement for a mevalonate-derived compound is exhibited by other types of mammalian cells which have been stimulated to undergo proliferation. Therefore the information obtained from this study should be useful in extending these studies to additional cell systems, particularly malignant and virally transformed cells; both of which show increased levels of HMG-CoA reductase activity or sterol synthesis. Many anti-cholesterolemic drugs inhibit cholesterol biosynthesis at the level of mevalonate synthesis. If mevalonate is required for lymphocyte activation, then drugs used to lower blood cholesterol levels may secondarily act as immunosuppressive agents. Experiments described in this proposal will test several anticholesterolemic drugs for their effect(s) on lymphocyte activation in vitro.